There is increasing interest in activating specific thyroid hormone signaling pathways in the brain for the treatment of certain CNS diseases, in particular those that involve defects in remyelination (Fourcade S et al, Mol Pharmacol 63, 1296-1303 (2003) and Baxi E G et al, Glia 62, 1513-1529 (2014); both of which are incorporated by reference herein). Thyroid hormones T4 and T3 are not suitable as therapeutics for these indications as there is no therapeutic index for T4 and T3 separating the desired therapeutic effect from adverse effects associated with hyperthyroidism such as tachycardia, muscle wasting, and osteoporosis (Yen P M et al, Physiol Rev 81, 1097-1142 (2001); Yen P M et al, Mol Cell Endocrinol 246, 121-127 (2006); Biondi B and Klein I, Endocrine 24, 1-13 (2004); and Klein I and Ojamaa K, Endocrinol Metab Clin North Am 27, 51-62 (1998); all of which are incorporated by reference herein) This issue is potentially addressed by selective thyromimetics which are synthetic T3 agonists that show tissue selective thyroid hormone action (Joharapurkar A A et al, J Med Chem 55, 5649-5675 (2012); incorporated by reference herein.)
Sobetirome (also known as GC-1) is an example that has been studied extensively over the past 15 years (Scanlan T S, Heart Fail Rev 15, 177-182 (2010); incorporated by reference herein). Like T3, sobetirome affects LDL cholesterol lowering by stimulating hepatic cholesterol clearance mechanisms, but unlike T3, does so at doses that have no deleterious effect on heart, muscle, or bone (Grover G J et al, Endocrinology 145, 1656-1661 (2004); incorporated by reference herein). This therapeutic index supports the idea of testing sobetirome for efficacy in neurological disease models. However, distribution to the CNS is an essential property for such a thyromimetic to be useful as a therapeutic agent. Therefore sobetirome derivatives with improved CNS distribution are needed.